Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Blood total antioxidant status is associated with cortical glucose uptake and factors related to accelerated aging

Abstract

Identifying cerebral vulnerability in late life is of paramount importance to prevent pathological trajectories of aging before the onset of symptoms. Considerable evidence suggests that impaired antioxidant mechanisms are a fingerprint of aging-related conditions, but there is a lack of human research linking total antioxidant capacity (TAC) measured in peripheral blood to in vivo brain changes and other factors featuring accelerated aging. To address this issue, we have assessed in cognitively normal elderly subjects (N = 100) correlations between serum TAC, using the oxygen radical absorbance capacity assay, surface-based cortical thickness, surface-based 18F-fluorodeoxyglucose positron emission tomography cortical uptake, and different factors associated with accelerated aging [i.e., serum homocysteine (HCY), self-reported memory problems, and self-reported patterns of physical activity]. While no relationship was observed between serum TAC and variations in cortical thickness, decreased TAC level was significantly associated with lower FDG uptake in temporal lobes bilaterally. Remarkably, decreased TAC level was linked to increased HCY concentrations, more subjective memory complaints, and lower frequency of physical activity. Overall, our results suggest that decreased serum TAC level may be helpful to detect vulnerable trajectories of aging.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. An Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O, Chia CW, Egan JM, Ferrucci L, Troncoso J, Levey AI, Lah J, Seyfried NT, Legido-Quigley C, O'Brien R, Thambisetty M (2018) Evidence for brain glucose dysregulation in Alzheimer's disease. Alzheimers Dement 14:318–329

  2. Behera J, Bala J, Nuru M, Tyagi SC, Tyagi N (2017) Homocysteine as a pathological biomarker for bone disease. J Cell Physiol 232:2704–2709

  3. Bell KF (2013) Insight into a neuron's preferential susceptibility to oxidative stress. Biochem Soc Trans 41:1541–1545

  4. Bernal-Rusiel JL, Atienza M, Cantero JL (2008) Detection of focal changes in human cortical thickness: spherical wavelets versus Gaussian smoothing. Neuroimage 41:1278–1292

  5. Bernal-Rusiel JL, Atienza M, Cantero JL (2010) Determining the optimal level of smoothing in cortical thickness analysis: a hierarchical approach based on sequential statistical thresholding. Neuroimage 52:158–171

  6. Bogdanovic N, Zilmer M, Zilmer K, Rehema A, Karelson E (2001) The Swedish APP670/671 Alzheimer's disease mutation: the first evidence for strikingly increased oxidative injury in the temporal inferior cortex. Dement Geriatr Cogn Disord 12(6):364–370

  7. Böhm P, Peña-Casanova J, Aguilar M, Hernandez G, Sol JM, Blesa R, NORMACODEN Group (1998) Clinical validity and utility of the interview for deterioration of daily living in dementia for Spanish-speaking communities. Int Psychogeriatr 10:261–270

  8. Borras C, Stvolinsky S, Lopez-Grueso R, Fedorova T, Gambini J, Boldyrev A, Viña J (2009) Low in vivo brain glucose consumption and high oxidative stress in accelerated aging. FEBS Lett 583:2287–2293

  9. Bowling AC, Mutisya EM, Walker LC, Price DL, Cork LC, Beal MF (1993) Age-dependent impairment of mitochondrial function in primate brain. J Neurochem 60:1964–1967

  10. Bürkle A, Moreno-Villanueva M, Bernhard J, Blasco M, Zondag G, Hoeijmakers JH, Toussaint O, Grubeck-Loebenstein B, Mocchegiani E, Collino S, Gonos ES, Sikora E, Gradinaru D, Dollé M, Salmon M, Kristensen P, Griffiths HR, Libert C, Grune T, Breusing N, Simm A, Franceschi C, Capri M, Talbot D, Caiafa P, Friguet B, Slagboom PE, Hervonen A, Hurme M, Aspinall R (2015) MARK-AGE biomarkers of ageing. Mech Ageing Dev 151:2–12

  11. Butterfield DA, Halliwell B (2019) Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 20:148–160

  12. Cantero JL, Iglesias JE, Van Leemput K, Atienza M (2016) Regional hippocampal atrophy and higher levels of plasma amyloid-beta are associated with subjective memory complaints in nondemented elderly subjects. J Gerontol A Biol Sci Med Sci 71:1210–1215

  13. Cantero JL, Zaborszky L, Atienza M (2017) Volume loss of the nucleus basalis of Meynert is associated with atrophy of innervated regions in mild cognitive impairment. Cereb Cortex 27:3881–3889

  14. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimerdisease. Arch Neurol 55:1449–1455

  15. da Cruz AC, Petronilho F, Heluany CC, Vuolo F, Miguel SP, Quevedo J, Romano-Silva MA, Dal-Pizzol F (2014) Oxidative stress and aging: correlation with clinical parameters. Aging Clin Exp Res 26:7–12

  16. Di Benedetto S, Müller L, Wenger E, Düzel S, Pawelec G (2017) Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions. Neurosci Biobehav Rev 75:114–128

  17. Di Meco A, Li JG, Barrero C, Merali S, Praticò D (2019) Elevated levels of brain homocysteine directly modulate the pathological phenotype of a mouse model of tauopathy. Mol Psychiatry 24:1696–1706

  18. Ding SL, Van Hoesen GW, Cassell MD, Poremba A (2009) Parcellation of human temporal polar cortex: a combined analysis of multiple cytoarchitectonic, chemoarchitectonic, and pathological markers. J Comp Neurol 514:595–623

  19. Done AJ, Traustadóttir T (2016) Aerobic exercise increases resistance to oxidative stress in sedentary older middle-aged adults. A pilot study. Age (Dordr) 38:505–512

  20. Dringen R, Gutterer JM, Hirrlinger J (2000) Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem 267:4912–4916

  21. Duelli R, Kuschinsky W (2001) Brain glucose transporters: relationship to local energy demand. News Physiol Sci 16:71–76

  22. Enciu AM, Gherghiceanu M, Popescu BO (2013) Triggers and effectors of oxidative stress at blood–brain barrier level: relevance for brain ageing and neurodegeneration. Oxid Med Cell Longev 2013:297512

  23. Evans PH (1993) Free radicals in brain metabolism and pathology. Br Med Bull 49:577–587

  24. Fischl B, Dale AM (2000) Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 97:11050–11055

  25. Gavillet M, Allaman I, Magistretti PJ (2008) Modulation of astrocytic metabolic phenotype by proinflammatory cytokines. Glia 56:975–989

  26. Gegg ME, Clark JB, Heales SJ (2005) Co-culture of neurones with glutathione deficient astrocytes leads to increased neuronal susceptibility to nitric oxide and increased glutamate-cysteine ligase activity. Brain Res 1036:1–6

  27. Godin G, Shephard RJ (1985) A simple method to assess exercise behavior in the community. Can J Appl Sport Sci 10:141–146

  28. Gonzalez S, Huerta JM, Fernandez S, Patterson AM, Lasheras C (2007) Homocysteine increases the risk of mortality in elderly individuals. Br J Nutr 97:1138–1143

  29. Goraca A (2004) Assessment of total antioxidant capacity in human plasma. Folia Med (Plovdiv) 46:16–21

  30. Grammas P, Martinez J, Miller B (2011) Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases. Expert Rev Mol Med 13:e19

  31. Guidi I, Galimberti D, Lonati S, Novembrino C, Bamonti F, Tiriticco M, Fenoglio C, Venturelli E, Baron P, Bresolin N, Scarpini E (2006) Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease. Neurobiol Aging 27:262–269

  32. Hengstermann S, Laemmler G, Hanemann A, Schweter A, Steinhagen-Thiessen E, Lun A, Schulz RJ (2008) Total serum homocysteine levels do not identify cognitive dysfunction in multimorbid elderly patients. J Nutr Health Aging 12:411–416

  33. Hooshmand B, Solomon A, Kåreholt I, Rusanen M, Hänninen T, Leiviskä J, Winblad B, Laatikainen T, Soininen H, Kivipelto M (2012) Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Int Med 271:204–212

  34. Jessen F, Amariglio RE, van Boxtel M, Breteler M, Ceccaldi M, Chételat G, Dubois B, Dufouil C, Ellis KA, van der Flier WM, Glodzik L, van Harten AC, de Leon MJ, McHugh P, Mielke MM, Molinuevo JL, Mosconi L, Osorio RS, Perrotin A, Petersen RC, Rabin LA, Rami L, Reisberg B, Rentz DM, Sachdev PS, de la Sayette V, Saykin AJ, Scheltens P, Shulman MB, Slavin MJ, Sperling RA, Stewart R, Uspenskaya O, Vellas B, Visser PJ, Wagner M, Subjective Cognitive Decline Initiative (SCD-I) Working Group (2014) A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimers Dement 10:844–852

  35. Ji LL, Leeuwenburgh C, Leichtweis S, Gore M, Fiebig R, Hollander J, Bejma J (1998) Oxidative stress and aging. Role of exercise and its influences on antioxidant systems. Ann N Y Acad Sci 854:102–117

  36. Kacem K, Lacombe P, Seylaz J, Bonvento G (1998) Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: a confocal microscopy study. Glia 23:1–10

  37. Kanani PM, Sinkey CA, Browning RL, Allaman M, Knapp HR, Haynes WG (1999) Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation 100:1161–1168

  38. Kang C, Chung E, Diffee G, Ji LL (2013) Exercise training attenuates aging-associated mitochondrial dysfunction in rat skeletal muscle: role of PGC-1α. Exp Gerontol 48:1343–1350

  39. Karelson E, Bogdanovic N, Garlind A, Winblad B, Zilmer K, Kullisaar T, Vihalemm T, Kairane C, Zilmer M (2001) The cerebrocortical areas in normal brain aging and in Alzheimer's disease: noticeable differences in the lipid peroxidation level and in antioxidant defense. Neurochem Res 26:353–361

  40. Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ, Wilson JM, DiStefano LM, Nobrega JN (1992) Brain cytochrome oxidase in Alzheimer's disease. J Neurochem 59:776–779

  41. Kohen R, Nyska A (2002) Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 30:620–650

  42. Kujovic M, Zilles K, Malikovic A, Schleicher A, Rottschy C, Mohlberg H, Eickhoff S, Amunts K (2013) Cytoarchitectonic mapping of the dorsal extrastriate human visual cortex. Brain Struct Funct 218:157–172

  43. Lean JM, Davies JT, Fuller K, Jagger CJ, Kirstein B, Partington GA, Urry ZL, Chambers TJ (2003) A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest 112:915–923

  44. Lehmann M, Gottfries CG, Regland B (1999) Identification of cognitive impairment in the elderly: homocysteine is an early marker. Dement Geriatr Cogn Disord 10:12–20

  45. Lhoták S, Zhou J, Austin RC (2011) Immunohistochemical detection of the unfolded protein response in atherosclerotic plaques. Methods Enzymol 489:23–46

  46. Lipton SA, Kim WK, Choi YB, Kumar S, D’Emilia DM, Rayudu PV, Arnelle DR, Stamler JS (1997) Neurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor. Proc Natl Acad Sci USA 94:5923–5928

  47. Low A, Mak E, Rowe JB, Markus HS, O'Brien JT (2019) Inflammation and cerebral small vessel disease: a systematic review. Ageing Res Rev 53:100916

  48. Lubos E, Loscalzo J, Handy DE (2007) Homocysteine and glutathione peroxidase-1. Antioxid Redox Signal 9:1923–1940

  49. McCully KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56:111–128

  50. McCully KS (2017) Hyperhomocysteinemia, suppressed immunity, and altered oxidative metabolism caused by pathogenic microbes in atherosclerosis and dementia. Front Aging Neurosci 2017(9):324

  51. McLean RR, Jacques PF, Selhub J, Tucker KL, Samelson EJ, Broe KE, Hannan MT, Cupples LA, Kiel DP (2004) Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 350:2042–2049

  52. Mooradian AD, Chung HC, Shah GN (1997) GLUT-1 expression in the cerebra of patients with Alzheimer's disease. Neurobiol Aging 18:469–474

  53. Morgello S, Uson RR, Schwartz EJ, Haber RS (1995) The human blood-brain barrier glucose transporter (GLUT1) is a glucose transporter of gray matter astrocytes. Glia 14:43–54

  54. Morley JE, Morris JC, Berg-Weger M, Borson S, Carpenter BD, Del Campo N, Dubois B, Fargo K, Fitten LJ, Flaherty JH, Ganguli M, Grossberg GT, Malmstrom TK, Petersen RD, Rodriguez C, Saykin AJ, Scheltens P, Tangalos EG, Verghese J, Wilcock G, Winblad B, Woo J, Vellas B (2015) Brain health: the importance of recognizing cognitive impairment: an IAGG consensus conference. J Am Med Dir Assoc 16:731–739

  55. Mosconi L, De Santi S, Brys M, Tsui WH, Pirraglia E, Glodzik-Sobanska L, Rich KE, Switalski R, Mehta PD, Pratico D, Zinkowski R, Blennow K, de Leon MJ (2008) Hypometabolism and altered cerebrospinal fluid markers in normal apolipoprotein E E4 carriers with subjective memory complaints. Biol Psychiatry 63:609–618

  56. Mutisya EM, Bowling AC, Beal MF (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J Neurochem 63:2179–2184

  57. Oelze M, Kröller-Schön S, Steven S, Lubos E, Doppler C, Hausding M, Tobias S, Brochhausen C, Li H, Torzewski M, Wenzel P, Bachschmid M, Lackner KJ, Schulz E, Münzel T, Daiber A (2014) Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging. Hypertension 63:390–396

  58. Ou B, Hampsch-Woodill M, Prior RL (2001) Development and validation of an improved oxygen radical absorbance capacity assay using fluorescein as the fluorescent probe. J Agric Food Chem 49:4619–4626

  59. Park HJ, Lee JD, Chun JW, Seok JH, Yun M, Oh MK, Kim JJ (2006) Cortical surface-based analysis of 18F-FDG PET: measured metabolic abnormalities in schizophrenia are affected by cortical structural abnormalities. Neuroimage 31:1434–1444

  60. Pascual JM, Van Heertum RL, Wang D, Engelstad K, De Vivo DC (2002) Imaging the metabolic footprint of Glut1 deficiency on the brain. Ann Neurol 52:458–464

  61. Perrotte M, Le Page A, Fournet M, Le Sayec M, Rassart É, Fulop T, Ramassamy C (2018) Blood-based redox-signature and their association to the cognitive scores in MCI and Alzheimer's disease patients. Free Radic Biol Med 130:499–511

  62. Rottschy C, Eickhoff SB, Schleicher A, Mohlberg H, Kujovic M, Zilles K, Amunts K (2007) Ventral visual cortex in humans: cytoarchitectonic mapping of two extrastriate areas. Hum Brain Mapp 28:1045–1059

  63. Rubenstein LZ (2006) Falls in older people: epidemiology, risk factors II and strategies for prevention. Age Ageing 35(Suppl 2):37–41

  64. Safdar A, Hamadeh MJ, Kaczor JJ, Raha S, Debeer J, Tarnopolsky MA (2010) Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults. PLoS ONE 5(5):e10778

  65. Saito M, Marumo K (2018) The effects of homocysteine on the skeleton. Curr Osteoporos Rep 16:554–560

  66. Sala I, Belen Sanchez-Saudinos M, Molina-Porcel L, Lazaro E, Gich I, Clarimon J, Blanco-Vaca F, Blesa R, Gomez-Isla T, Lleo A (2008) Homocysteine and cognitive impairment. Relation with diagnosis and neuropsychological performance. Dement Geriatr Cogn Disord 26:506–512

  67. Sanchez-Espinosa MP, Atienza M, Cantero JL (2017) Sleep mediates the association between homocysteine and oxidative status in mild cognitive impairment. Sci Rep 7(1):7719

  68. Sanchez-Rodriguez MA, Ruiz-Ramos M, Correa-Muñoz E, Mendoza-Nuñez VM (2007) Oxidative stress as a risk factor for osteoporosis in elderly Mexicans as characterized by antioxidant enzymes. BMC Musculoskelet Disord 19(8):124

  69. Schroeter ML, Mertsch K, Giese H, Müller S, Sporbert A, Hickel B, Blasig IE (1999) Astrocytes enhance radical defence in capillary endothelial cells constituting the blood–brain barrier. FEBS Lett 449:241–244

  70. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346:476–483

  71. Shafto MA, Stamatakis EA, Tam PP, Tyler LK (2010) Word retrieval failures in old age: the relationship between structure and function. J Cogn Neurosci 22:1530–1540

  72. Shirafuji N, Hamano T, Yen SH, Kanaan NM, Yoshida H, Hayashi K, Ikawa M, Yamamura O, Kuriyama M, Nakamoto Y (2018) Homocysteine increases tau phosphorylation, truncation and oligomerization. Int J Mol Sci 19(3):891

  73. Shukla A, Dikshit M, Srimal RC (1995) Status of antioxidants in brain microvessels of monkey and rat. Free Radic Res 22:303–308

  74. Simonian NA, Hyman BT (1993) Functional alterations in Alzheimer's disease: diminution of cytochrome oxidase in the hippocampal formation. J Neuropathol Exp Neurol 52(6):580–585

  75. Simpson IA, Chundu KR, Davies-Hill T, Honer WG, Davies P (1994) Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease. Ann Neurol 35:546–551

  76. Siqueira IR, Fochesatto C, de Andrade A, Santos M, Hagen M, Bello-Klein A, Netto CA (2005) Total antioxidant capacity is impaired in different structures from aged rat brain. Int J Dev Neurosci 23:663–671

  77. Souza DG, Bellaver B, Raupp GS, Souza DO, Quincozes-Santos A (2015) Astrocytes from adult Wistar rats aged in vitro show changes in glial functions. Neurochem Int 90:93–97

  78. Suszyńska-Zajczyk J, Luczak M, Marczak L, Jakubowski H (2014) Hyperhomocysteinemia and bleomycin hydrolase modulate the expression of mouse brain proteins involved in neurodegeneration. J Alzheimers Dis 40:713–726

  79. Tolppanen AM, Solomon A, Kulmala J, Kåreholt I, Ngandu T, Rusanen M, Laatikainen T, Soininen H, Kivipelto M (2015) Leisure-time physical activity from mid- to late life, body mass index, and risk of dementia. Alzheimers Dement 11:434–443

  80. Traustadóttir T, Davies SS, Su Y, Choi L, Brown-Borg HM, Roberts LJ 2nd, Harman SM (2012) Oxidative stress in older adults: effects of physical fitness. Age (Dordr) 34:969–982

  81. United Nations, Department of Economic and Social Affairs, Population Division (2017) World population prospects: the 2017 revision, key findings and advance tables. Working Paper No. ESA/P/WP/248

  82. Valla J, Berndt JD, Gonzalez-Lima F (2001) Energy hypometabolism in posterior cingulate cortex of Alzheimer's patients: superficial laminar cytochrome oxidase associated with disease duration. J Neurosci 21:4923–4930

  83. van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, van der Klift M, de Jonge R, Lindemans J, de Groot LC, Hofman A, Witteman JC, van Leeuwen JP, Breteler MM, Lips P, Pols HA, Uitterlinden AG (2004) Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 350:2033–2041

  84. Venkateshappa C, Harish G, Mahadevan A, Srinivas Bharath MM, Shankar SK (2012) Elevated oxidative stress and decreased antioxidant function in the human hippocampus and frontal cortex with increasing age: implications for neurodegeneration in Alzheimer's disease. Neurochem Res 37:1601–1614

  85. Weiss N, Heydrick SJ, Postea O, Keller C, Keaney JF Jr, Loscalzo J (2003) Influence of hyperhomocysteinemia on the cellular redox state—impact on homocysteine-induced endothelial dysfunction. Clin Chem Lab Med 41:1455–1461

  86. Welch GN, Upchurch GR Jr, Loscalzo J (1997) Homocysteine, oxidative stress, and vascular disease. Hosp Pract 32:81–92

  87. Wong-Riley MT (1989) Cytochrome oxidase: an endogenous metabolic marker for neuronal activity. Trends Neurosci 12:94–101

  88. Wyss-Coray T (2016) Ageing, neurodegeneration and brain rejuvenation. Nature 539:180–186

  89. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, Leirer VO (1983) Development and validation of a geriatric depression scale: a preliminary report. J Psychiat Res 17:37–49

  90. Yilmaz N, Eren E (2009) Homocysteine oxidative stress and relation to bone mineral density in post-menopausal osteoporosis. Aging Clin Exp Res 21:353–357

  91. Zhuo JM, Portugal GS, Kruger WD, Wang H, Gould TJ, Praticò D (2010) Diet-induced hyperhomocysteinemia increases amyloid-beta formation and deposition in a mouse model of Alzheimer’s disease. Curr Alzheimer Res 7:140–149

Download references

Funding

This work was supported by research Grants from the Spanish Ministry of Economy and Competitiveness (SAF2017-85310-R to JLC, PSI2017-85311-P to MA); the Regional Ministry of Innovation, Science and Enterprise, Junta de Andalucia (P12-CTS-2327 to JLC); the International Center on Aging CENIE-POCTEP (0348_CIE_6_E to MA); and CIBERNED (CB06/05/1111 to JLC).

Author information

Correspondence to Jose L. Cantero.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of Ethics Committee for Human Research of the Pablo de Olavide University and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Palomar-Bonet, M., Atienza, M. & Cantero, J.L. Blood total antioxidant status is associated with cortical glucose uptake and factors related to accelerated aging. Brain Struct Funct (2020). https://doi.org/10.1007/s00429-020-02039-0

Download citation

Keywords

  • Aging
  • Blood total antioxidant capacity
  • Cortical thickness
  • FDG-PET
  • Homocysteine
  • Subjective memory complaints
  • Physical activity